Management of Niemann-Pick type C disease
As Niemann-Pick type C disease (NP-C) is a progressive disease, early diagnosis is critical to ensure that patients can start disease-specific therapy to stabilize or delay disease progression and preserve function and quality of life, which without a cure, are the best attainable treatment goals for NP-C. Management strategies also include non-specific, symptomatic treatments.1
Recent advances in the understanding of NP-C pathophysiology have led to the development of a NP-C-specific treatment that can have an impact on disease progression. In January 2009, a glycosphingolipid synthesis inhibitor called Zavesca® (miglustat) was approved in the European Union (EU) and is now available in a total of 52 countries, for the treatment of progressive neurologic manifestations in adult and pediatric patients with NP-C.2 By inhibiting the enzyme glucosylceramide synthase, this therapy prevents the synthesis of glycosphingolipids and in doing so reduces the accumulation of these lipids in patients with NP-C. It has been shown that miglustat can improve or stabilize key parameters of progressive neurologic disease in children, juveniles and adult patients, including saccadic eye movements, ability to swallow, auditory acuity, ambulation, manipulation, language, dystonia, dysmetria, dysarthria, developmental delay/cognitive impairment, disability status, and rate of structural brain changes.3–10
Extension treatment studies have shown that therapeutic benefits of miglustat were maintained for the entire observational period of up to 48 months.11
Disease-specific therapy should be initiated at the earliest sign of neurologic disease onset in order to optimize treatment outcomes.1
The most frequently reported adverse events of miglustat therapy were mild or moderate diarrhea, flatulence, abdominal pain, weight loss and tremor.2 Gastrointestinal disturbances and weight loss tend to decrease over time on continued therapy and can be managed by dietary modification where foods containing disaccharides are reduced, temporary dose reduction or co-administration of probiotics such as saccharomyces boulardii and symptomatic therapy, such as loperamide.2
Symptomatic therapies may be at least partially successful in treating some symptoms of NP-C. Although they have no impact on disease progression or long-term outcomes, they can improve the patient’s quality of life. The main approaches to management of the visceral, neurologic, and psychiatric symptoms of NP-C are summarized in Figure 1.1.
Figure 1: Symptomatic treatment of NP-C.1
|Visceral (systemic) symptoms|
|Gastrointestinal disturbances||Anti-propulsive agents, such as loperamide for diarrhea; a bowel management programme to prevent constipation|
|Lung symptoms||Aggressive bronchodilatation; chest physical therapy|
Softening or thickening of food; gastrostomy
|Oral atropine; parotid or sub-malar injections of botulinum toxin; hyoscine patches or glycopyrronium bromide|
|Cataplexy||Tricyclic antidepressants; CNS stimulants|
|Anticholinergic drugs; benzodiazepines; botulinum toxin (selected cases only); gamma-aminobutyric acid derivatives (advanced dystonia)|
|Sleep disorders||Melatonin; positive airway pressure|
|Movement restrictions||Physical therapy|
|Seizures||Antiepileptic drugs, according to seizure type|
|Bipolar disorder||Mood stabilizers, such as sodium valproate|
|Catatonia||Electroconvulsive therapy (ECT)|
|Depression||Selective serotonin reuptake inhibitors (SSRIs)|
Potential future therapies
Several other approaches to the management of NP-C have been or are currently being assessed for their potential use in the treatment of NP-C.
- Patterson MC, Hendriksz CJ, Walterfang M, et al., on behalf of the NP-C Guidelines Working Group. Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update. Mol Genet Metab 2012;106:330–44.
- Zavesca® Summary of Product Characteristics.
- Patterson MC, Vecchio D, Prady H, et al. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 2007;6:765–72.
- Pineda M, Wraith JE, Mengel E, et al. Miglustat in patients with Niemann-Pick disease Type C (NP-C): A multicenter observational retrospective cohort study. Mol Genet Metab 2009;98:243–9.
- Patterson MC, Vecchio D, Jacklin E, et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol 2009;25:300-5.
- Abel LA, Walterfang M, Stainer MJ, et al. Longitudinal assessment of reflexive and volitional saccades in Niemann-Pick Type C disease during treatment with miglustat. Orphanet J Rare Dis 2015;10:160.
- Fecarotta S, Romano A, Della Cassa R, et al. Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann-Pick disease type C. Orphanet J Rare Dis 2015;10:22.
- Patterson MC, Mengel E, Vanier MT, et al. Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. Orphanet J Rare Dis 2015;10:65.
- Ginocchio VM, D'Amico A, Bertini E, et al. Efficacy of Miglustat in Niemann–Pick C disease: A single centre experience. Mol Genet Metab 2013;110:329–35.
- Bowman EA, Walterfang M, Abel LA, et al. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann–Pick disease type C patients treated with miglustat. J Neurol 2015;262:2106–14.
- Wraith JE, Vecchio D, Jacklin E, et al. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab 2010;99:351–7.
- Patterson MC, Mengel E, Wijburg FA, et al. Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet J Rare Dis 2013;8:12.
- Patterson MC, Mengel E, Vanier MT, et al. Stale or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. Orphanet J Rare Dis 2015;10:65.
- Imrie J, Heptinstall L, Knight S, Strong K. Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-years update form the UK clinical database. BMC Neurol 2015;15:257.